Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study

International Journal of Impotence Research volume 19, pages 200–207 (2007)Cite this article

Abstract

Men with erectile dysfunction (ED) frequently have a disproportionate burden of comorbid vascular disorders including atherosclerotic disease. We investigated whether scheduled tadalafil is better than on-demand (OD) in improving endothelium-dependent vasodilatation of cavernous arteries in men with ED and whether this effect is also exerted on markers of endothelial function. We did an open-label, randomized, crossover study including 20 male outclinic patients aged 18 years or older (mean age 54 years) who had at least a 3-month history of ED of any severity or etiology. Tadalafil (20 mg) on alternate days (ADs) or OD was administered for 4 weeks. Primary end points were variations of basal inflow (peak systolic velocity (PSV)) and flow-mediated dilatation (FMD) of cavernous arteries compared with baseline at penile Duplex ultrasound. Secondary end points were variations of Q13-SIEDY scores regarding morning erections and of markers of endothelial function, that is, vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule, endothelin-1 (ET-1), insulin and C-reactive protein (CRP). PSVs and FMD were higher after AD treatment when compared with OD and baseline, respectively (P=0.0001), and improvements were maintained from 2 weeks after discontinuation (P<0.005). Patients receiving tadalafil AD experienced a significant improvement of morning erections as compared to AD treatment (P<0.0001); ET1, VCAM and CRP showed a robust decrease after chronic vs OD regimes (P<0.05), with concomitant increase in insulin levels (P<0.05), without any variation in blood pressure and other laboratory parameters. Chronic but not OD tadalafil improves endothelial function with sustained effects from its discontinuation. Chronic treatment also produces a dramatic increase in morning erections, which determines better oxygenation to the penis, thus providing a rationale for vascular rehabilitation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Flavahan NA . Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity. Circulation 1992; 85 (5): 1927–1938.

    Article  CAS  Google Scholar 

  2. Ross R . The pathogenesis of atherosclerosis: a perspective for 1990s. Nature 1993; 362: 801–809.

    Article  CAS  Google Scholar 

  3. Panza JA, Quyyumi AA, Brush JE, Epstein SE . Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323: 22–27.

    Article  CAS  Google Scholar 

  4. Schächinger V, Britten MB, Zeiher AM . Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101: 1899.

    Article  Google Scholar 

  5. Virag R, Floresco J, Richard C . Impairment of shear-stress mediated vasodilatation of cavernous arteries in erectile dysfunction. Int J Impot Res 2004; 16: 39–42.

    Article  CAS  Google Scholar 

  6. Soloman H, Man JW, Jackson G . Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003; 89: 251–254.

    Article  Google Scholar 

  7. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB . Impotence and its medical and psychological correlates: results of the Massachusetts Male Ageing Study. J Urol 1994; 151: 54–61.

    Article  CAS  Google Scholar 

  8. Hale TM, Shoichet MJ, Bushfield TL, Adams MA . Time course of vascular structural changes during and after short-term antihypertensive treatment. Hypertension 2003; 42: 171–177.

    Article  CAS  Google Scholar 

  9. Hale TM, Okabe H, Heaton JP, Adams MA . Antihypertensive drugs induce structural remodeling of penile vasculature. J Urol 2001; 166 (2): 739–745.

    Article  CAS  Google Scholar 

  10. Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G . Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 2005; 47: 214–222.

    Article  CAS  Google Scholar 

  11. Petrone L, Mannucci E, Corona G, Bartolini M, Forti G, Giommi R et al. Semi-Structured Interview on Erectile Dysfunction (SIEDY): a new, multidimensional instrument for quantification of pathogenetic issues on erectile dysfunction. Int J Impot Res 2003; 15 (3): 210–220.

    Article  CAS  Google Scholar 

  12. Aversa A, Bonifacio V, Moretti C, Frajese G, Fabbri A . Re-dosing of prostaglandin-E1 versus prostaglandin-E1 plus phentolamine in male erectile dysfunction: a dynamic color power Doppler study. Int J Impot Res 2000; 12 (1): 33–40.

    Article  CAS  Google Scholar 

  13. Poli A, Tremoli L, Colombo A, Sintori M, Pignoli P, Paoletti R . Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients: a new for the quantitation and follow-up of preclinical atherosclerosis in living subjects. Atherosclerosis 1988; 20: 253–261.

    Article  Google Scholar 

  14. Kukreja RC, Ockaili R, Salloum F, Xi L . Sildenafil-induced cardioprotection in rabbits. Circulation Res 2003; 60: 700–701.

    CAS  Google Scholar 

  15. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R . Metabolic syndrome. A comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 2005; 111: 1448–1454.

    Article  Google Scholar 

  16. Takebayashi K, Aso Y, Inukai T . Initiation of insulin therapy reduces serum concentrations of high-sensitivity C-reactive protein in patients with type 2 diabetes. Metabolism 2004; 53: 693–699.

    Article  CAS  Google Scholar 

  17. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE . Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 2004; 53: 2079–2086.

    Article  CAS  Google Scholar 

  18. Mazo E, Gamidov S, Iremashvili I . The effect of vardenafil on endothelial function of brachial and cavernous arteries. Int J Impot Res 2006 (advance online publication, 16 February 2006).

  19. Foresta C, Ferlin A, De Toni L, Lana A, Vinanzi C, Galan A et al. Circulating endothelial progenitor cells and endothelial function after chronic tadalafil treatment in subjects with erectile dysfunction. Int J Impot Res 2006 (advance online publication, 16 March 2006).

  20. Jonassen AK, Sack MN, Mjos OD, Yellon DM . Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circulation Res 2001; 89: 1191–1198.

    Article  CAS  Google Scholar 

  21. Ahmad M, Abdel-Wahab YH, Tate R, Flatt PR, Pyne NJ, Furman BL . Effect of type-selective inhibitors on cyclic nucleotide phosphodiesterase activity and insulin secretion in the clonal insulin secreting cell line BRIN-BD11. Br J Pharmacol 2000; 129 (6): 1228–1234.

    Article  CAS  Google Scholar 

  22. Kang KK, Yu JY, Yoo M, Kwon JW . The effect of DA-8159, a novel PDE5 inhibitor, on erectile function in the rat model of hypercholesterolemic erectile dysfunction. Int J Impot Res 2005; 17 (5): 409–416.

    Article  CAS  Google Scholar 

  23. Ahn GJ, Yu JY, Choi SM, Kang KK, Ahn BO, Kwon JW et al. Chronic administration of phosphodiesterase 5 inhibitor improves erectile and endothelial function in a rat model of diabetes. Int J Androl 2005; 28 (5): 260–266.

    Article  CAS  Google Scholar 

  24. Robinson SD, Ludlam CA, Boon NA, Newby DE . Phosphodiesterase type 5 inhibition does not reverse endothelial dysfunction in patients with coronary heart disease. Heart 2006; 92 (2): 170–176.

    Article  CAS  Google Scholar 

  25. Kaiser DR, Billups K, Mason C, Wetterling R, Lundberg JR, Bank AJ . Impaired brachial artery, endothelium dependent and independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol 2004; 43: 179–184.

    Article  Google Scholar 

  26. Kostis JB, Jackson G, Rosen R, Barret-Connor E, Billups K, Burnett AL et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol 2005; 96 (12B): 85M–93M.

    Article  Google Scholar 

  27. Montorsi F, Briganti A, Salonia A, Rigatti P, Margonato A, Macchi A et al. Erectile dysfunction prevalence, time of onset and association with risk factor in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003; 44 (3): 360–365.

    Article  Google Scholar 

  28. Kim SW, Paick J, Park DW, Chae I, Oh B . Potential predictors of asymptomatic ischemic heart disease in patient with vasculogenic erectile dysfunction. Urology 2001; 58 (3): 441–445.

    Article  CAS  Google Scholar 

  29. Shamloul R, Ghanem HM, Salem A, Elnashaar A, Elnaggar W, Darwish H et al. Correlation between penile Duplex findings and stress electrocardiography in men with erectile dysfunction. Int J Impot Res 2004; 16 (3): 235–237.

    Article  CAS  Google Scholar 

  30. Aversa A, Rocchietti-March M, Caprio M, Giannini D, Isidori A, Fabbri A . Anxiety-induced failure in erectile response to intracorporeal prostaglandin-E1 in non-organic male impotence: a new diagnostic approach. Int J Androl 1996; 19 (5): 307–313.

    Article  CAS  Google Scholar 

  31. Mancini M, Bartolini M, Maggi M, Innocenti P, Villari N, Forti G . Duplex ultrasound evaluation of cavernosal peak systolic velocity and waveform acceleration in the penile flaccid state: clinical significance in the assessment of the arterial supply in patients with erectile dysfunction. Int J Androl 2000; 23 (4): 199–204.

    Article  CAS  Google Scholar 

  32. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104: 424–428.

    Article  CAS  Google Scholar 

  33. Davignon J, Ganz P . Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109 (3): III-27–III-32.

    Google Scholar 

  34. Tokatli Z, Akand M, Yaman O, Gulpinar O, Anafarta K . Comparison of international index of erectile function with nocturnal penile tumescence and rigidity testing in evaluation of erectile dysfunction. Int J Impot Res 2006; 18 (2): 186–189.

    Article  CAS  Google Scholar 

  35. Aversa A, Basciani S, Visca P, Arizzi M, Gnessi L, Frajese G et al. Platelet-derived growth-factor (PDGF) and PDGF-receptors in rat corpus cavernosum: changes in expression after transient in vivo hypoxia. J Endocrinol 2001; 170 (2): 395–402.

    Article  CAS  Google Scholar 

  36. Nehra A, Goldstein I, Pabby A, Nugent M, Huang YH, De las Morenas A et al. Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J Urol 1996; 156: 1320–1329.

    Article  CAS  Google Scholar 

  37. El-Sakka AI, Hassoba HM, Pillarisetty RJ, Dahiya R, Lue TF . Peyronie's disease is associated with an increase in transforming growth factor-β protein expression. J Urol 1997; 158: 1391–1394.

    Article  CAS  Google Scholar 

  38. Montorsi F, Maga T, Strambi LF, Salonia A, Barbieri L, Scattoni V et al. Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology 2000; 56 (6): 906–911.

    Article  CAS  Google Scholar 

  39. Mirone V, Costa P, Damber JE, Holmes S, Moncada I, Van Ahlen H et al. An evaluation of an alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14 European countries. Eur Urol 2005; 47 (6): 846–854.

    Article  CAS  Google Scholar 

  40. Porst H, Giuliano F, Glina S, Ralph D, Casabé AR, Mboussa AE et al. 2006 Evaluation of the efficacy and safety of once-a-day dosing of tadalafil 5 mg and 10 mg in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol 2006 (advance online publication, 21 March 2006).

  41. Dishy V, Sofowora G, Harris PA, Kandcer M, Zhan F, Wood AJ et al. The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men. Clin Pharmacol Ther 2001; 70: 270–279.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Daniele Gianfrilli for precious collaboration in performing ultrasound studies.

Author information

Authors and Affiliations

  1. Medical Pathophysiology, University of Rome La Sapienza, Rome, Italy

    A Aversa, E Greco, R Bruzziches, M Pili, G Rosano & G Spera

Authors
  1. A Aversa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Greco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Bruzziches
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Pili
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Rosano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Spera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Aversa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aversa, A., Greco, E., Bruzziches, R. et al. Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res 19, 200–207 (2007). https://doi.org/10.1038/sj.ijir.3901513

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijir.3901513

Keywords

This article is cited by

Search

Advanced search

Quick links